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• W684291 abstract "Although the roles of survivin in control of cancer cell division and apoptosis as well as targeting survivin for cancer therapeutics have been extensively explored and reviewed, the pathophysiological role of survivin in normal human cells/organs has not been deeply investigated or sufficiently reviewed. Studies in the latter area, however, appear to be important for the identification of different mechanisms of regulation and function of survivin in normal versus abnormal cells and tissues (including cancer), which might ultimately provide the basis for novel approaches for disease treatment with low toxicity. This Review is intended to summarize current observations in the literature related to the physiological and/or pathological roles for survivin in various normal human cells or organs. Our view of potential future research directions for survivin pertinent to potential therapeutic applications will also be discussed. Although the roles of survivin in control of cancer cell division and apoptosis as well as targeting survivin for cancer therapeutics have been extensively explored and reviewed, the pathophysiological role of survivin in normal human cells/organs has not been deeply investigated or sufficiently reviewed. Studies in the latter area, however, appear to be important for the identification of different mechanisms of regulation and function of survivin in normal versus abnormal cells and tissues (including cancer), which might ultimately provide the basis for novel approaches for disease treatment with low toxicity. This Review is intended to summarize current observations in the literature related to the physiological and/or pathological roles for survivin in various normal human cells or organs. Our view of potential future research directions for survivin pertinent to potential therapeutic applications will also be discussed. Increasing evidence indicates that the unique member of the inhibitor of apoptosis (IAP) protein family, survivin,1Li F Survivin study: what is the next wave?.J Cell Physiol. 2003; 197: 8-29Crossref PubMed Scopus (305) Google Scholar is not only an essential protein molecule for the regulation of progression of mitosis, apoptosis inhibition, and drug/radiation resistance in various cancer cells,2Li F Ling X Survivin study: an update of “What is the next wave?”.J Cell Physiol. 2006; ([E-pub ahead of print])Google Scholar but it also plays a role in certain physiological processes as well as in pathological conditions in many human organs/cells. Based on observations from the current literature, this includes roles of survivin in embryonic development, hematopoietic cell survival/proliferation, T-cell development/maturation, and the pathophysiology of brain, liver, pancreas, gastrointestinal tract, testis, endometrium, and placenta. The pathophysiological roles for survivin in normal human organs or cells to be presented in this Review are summarized in Table 1. The potential role for survivin in normal tissues or cells raises the critical question as to whether targeting survivin for cancer treatment would be toxic to normal human cells/tissues. Evidence derived from studies of in vitro normal/cancerous human cells and in vivo xenograft animal models with human cancer cells suggests that interference of the expression and/or function of survivin in human cancer cells induced apoptosis and inhibited tumor growth with little toxicity to normal cells/organs.1Li F Survivin study: what is the next wave?.J Cell Physiol. 2003; 197: 8-29Crossref PubMed Scopus (305) Google Scholar, 2Li F Ling X Survivin study: an update of “What is the next wave?”.J Cell Physiol. 2006; ([E-pub ahead of print])Google Scholar, 3Altieri DC Validating survivin as a cancer therapeutic target.Nat Rev Cancer. 2003; 3: 46-54Crossref PubMed Scopus (1094) Google Scholar Specifically, adenoviral delivery of the survivin dominant-negative mutant in cancer cells induced apoptotic cell death but did not affect cell viability of proliferating normal human cells, including fibroblasts, endothelial cells, or smooth muscle cells.4Mesri M Wall NR Li J Kim RW Altieri DC Cancer gene therapy using a survivin mutant adenovirus.J Clin Invest. 2001; 108: 981-990Crossref PubMed Scopus (354) Google Scholar Importantly, in vivo studies of a xenograft mouse model revealed that interference of survivin expression and/or functions by therapeutic inhibitors showed no toxicity to mice.5O'Connor DS Wall NR Porter AC Altieri DC A p34(cdc2) survival checkpoint in cancer.Cancer Cell. 2002; 2: 43-54Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, 6Wall NR O'Connor DS Plescia J Pommier Y Altieri DC Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis.Cancer Res. 2003; 63: 230-235PubMed Google Scholar Recently, Plescia et al7Plescia J Salz W Xia F Pennati M Zaffaroni N Daidone MG Meli M Dohi T Fortugno P Nefedova Y Gabrilovich DI Colombo G Altieri DC Rational design of shepherdin, a novel anticancer agent.Cancer Cell. 2005; 7: 457-468Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar reported that a cell-permeable peptidomimetic of survivin (designated shepherdin), which functionally disrupts the interaction of heat shock protein 90 with survivin, Akt, and CDK6, effectively induces cancer cell death in vitro regardless of cell cycle status, p53 status, or Bcl-2 overexpression. However, this molecule did not affect colony formation of purified hematopoietic progenitor cells, and systematic administration of this molecule in mice effectively inhibited human xenograft tumor growth without observable toxicity.7Plescia J Salz W Xia F Pennati M Zaffaroni N Daidone MG Meli M Dohi T Fortugno P Nefedova Y Gabrilovich DI Colombo G Altieri DC Rational design of shepherdin, a novel anticancer agent.Cancer Cell. 2005; 7: 457-468Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar In addition, immunotherapy with a survivinDNA vaccine activated immune responses without effects on wound healing and fertility of mice,8Xiang R Mizutani N Luo Y Chiodoni C Zhou H Mizutani M Ba Y Becker JC Reisfeld RA A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication.Cancer Res. 2005; 65: 553-561PubMed Google Scholar and treatment of melanoma patients was not associated with toxicity.9Otto K Andersen MH Eggert A Keikavoussi P Pedersen LO Rath JC Bock M Brocker EB Straten PT Kampgen E Becker JC Lack of toxicity of therapy-induced T cell responses against the universal tumour antigen survivin.Vaccine. 2005; 23: 884-889Crossref PubMed Scopus (103) Google ScholarTable 1Summary of the Pathophysiological Role for Survivin in Normal Human Organs or CellsOrgans or cells with survivin positivityPhysiological roles of survivinPathological roles of survivinEmbryos and oocytesDevelopment/morphogenesis: cell cycle/mitosis,14Murphy CR Sabel JL Sandler AD Dagle JM Survivin mRNA is down-regulated during early Xenopus laevis embryogenesis.Dev Dyn. 2002; 225: 597-601Crossref PubMed Scopus (18) Google Scholar, 15Uren AG Wong L Pakusch M Fowler KJ Burrows FJ Vaux DL Choo KH Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype.Curr Biol. 2000; 10: 1319-1328Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar, 16Conway EM Pollefeyt S Steiner-Mosonyi M Luo W Devriese A Lupu F Bono F Leducq N Dol F Schaeffer P Collen D Herbert JM Deficiency of survivin in transgenic mice exacerbates Fas-induced apoptosis via mitochondrial pathways.Gastroenterology. 2002; 123: 619-631Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 17Kawamura K Sato N Fukuda J Kodama H Kumagai J Tanikawa H Shimizu Y Tanaka T Survivin acts as an antiapoptotic factor during the development of mouse preimplantation embryos.Dev Biol. 2003; 256: 331-341Crossref PubMed Scopus (72) Google Scholar apoptosis14Murphy CR Sabel JL Sandler AD Dagle JM Survivin mRNA is down-regulated during early Xenopus laevis embryogenesis.Dev Dyn. 2002; 225: 597-601Crossref PubMed Scopus (18) Google Scholar, 17Kawamura K Sato N Fukuda J Kodama H Kumagai J Tanikawa H Shimizu Y Tanaka T Survivin acts as an antiapoptotic factor during the development of mouse preimplantation embryos.Dev Biol. 2003; 256: 331-341Crossref PubMed Scopus (72) Google Scholar, 18Jiang Y de Bruin A Caldas H Fangusaro J Hayes J Conway EM Robinson ML Altura RA Essential role for survivin in early brain development.J Neurosci. 2005; 25: 6962-6970Crossref PubMed Scopus (106) Google ScholarLoss of survivin: mitotic defect/embryonic lethality,15Uren AG Wong L Pakusch M Fowler KJ Burrows FJ Vaux DL Choo KH Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype.Curr Biol. 2000; 10: 1319-1328Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar, 16Conway EM Pollefeyt S Steiner-Mosonyi M Luo W Devriese A Lupu F Bono F Leducq N Dol F Schaeffer P Collen D Herbert JM Deficiency of survivin in transgenic mice exacerbates Fas-induced apoptosis via mitochondrial pathways.Gastroenterology. 2002; 123: 619-631Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar apoptosis17Kawamura K Sato N Fukuda J Kodama H Kumagai J Tanikawa H Shimizu Y Tanaka T Survivin acts as an antiapoptotic factor during the development of mouse preimplantation embryos.Dev Biol. 2003; 256: 331-341Crossref PubMed Scopus (72) Google Scholar, 18Jiang Y de Bruin A Caldas H Fangusaro J Hayes J Conway EM Robinson ML Altura RA Essential role for survivin in early brain development.J Neurosci. 2005; 25: 6962-6970Crossref PubMed Scopus (106) Google ScholarHematopoietic cells (bone marrow)Cell cycle entry/proliferation,22Fukuda S Pelus LM Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34(+) cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis.Blood. 2001; 98: 2091-2100Crossref PubMed Scopus (196) Google Scholar, 24Fukuda S Foster RG Porter SB Pelus LM The antiapoptosis protein survivin is associated with cell cycle entry of normal cord blood CD34(+) cells and modulates cell cycle and proliferation of mouse hematopoietic progenitor cells.Blood. 2002; 100: 2463-2471Crossref PubMed Scopus (124) Google Scholar maturation,25Altznauer F Martinelli S Yousefi S Thurig C Schmid I Conway EM Schoni MH Vogt P Mueller C Fey MF Zangemeister-Wittke U Simon HU Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils.J Exp Med. 2004; 199: 1343-1354Crossref PubMed Scopus (157) Google Scholar, 26Gurbuxani S Xu Y Keerthivasan G Wickrema A Crispino JD Differential requirements for survivin in hematopoietic cell development.Proc Natl Acad Sci USA. 2005; 102: 11480-11485Crossref PubMed Scopus (84) Google Scholar survival22Fukuda S Pelus LM Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34(+) cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis.Blood. 2001; 98: 2091-2100Crossref PubMed Scopus (196) Google Scholar, 25Altznauer F Martinelli S Yousefi S Thurig C Schmid I Conway EM Schoni MH Vogt P Mueller C Fey MF Zangemeister-Wittke U Simon HU Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils.J Exp Med. 2004; 199: 1343-1354Crossref PubMed Scopus (157) Google Scholar, 26Gurbuxani S Xu Y Keerthivasan G Wickrema A Crispino JD Differential requirements for survivin in hematopoietic cell development.Proc Natl Acad Sci USA. 2005; 102: 11480-11485Crossref PubMed Scopus (84) Google ScholarLoss of survivin: impairment of proliferation, maturation, and apoptosis22Fukuda S Pelus LM Regulation of the inhibitor-of-apoptosis family member survivin in normal cord blood and bone marrow CD34(+) cells by hematopoietic growth factors: implication of survivin expression in normal hematopoiesis.Blood. 2001; 98: 2091-2100Crossref PubMed Scopus (196) Google Scholar, 23Fukuda S Pelus LM Elevation of survivin levels by hematopoietic growth factors occurs in quiescent CD34(+) hematopoietic stem and progenitor cells before cell cycle entry.Cell Cycle. 2002; 1: 322-326Crossref PubMed Scopus (50) Google Scholar, 24Fukuda S Foster RG Porter SB Pelus LM The antiapoptosis protein survivin is associated with cell cycle entry of normal cord blood CD34(+) cells and modulates cell cycle and proliferation of mouse hematopoietic progenitor cells.Blood. 2002; 100: 2463-2471Crossref PubMed Scopus (124) Google Scholar; excessive survivin: inflammatory diseases,19Li F Role of survivin and its splice variants in tumorigenesis.Br J Cancer. 2005; 92: 212-216Crossref PubMed Scopus (21) Google Scholar leukemia1Li F Survivin study: what is the next wave?.J Cell Physiol. 2003; 197: 8-29Crossref PubMed Scopus (305) Google Scholar, 2Li F Ling X Survivin study: an update of “What is the next wave?”.J Cell Physiol. 2006; ([E-pub ahead of print])Google Scholar, 3Altieri DC Validating survivin as a cancer therapeutic target.Nat Rev Cancer. 2003; 3: 46-54Crossref PubMed Scopus (1094) Google ScholarT lymphocytes (thymus)Maturation,31Kobayashi Y Yukiue H Sasaki H Fukai I Yokoyama T Kiriyama M Yamakawa Y Maeda M Fujii Y Developmentally regulated expression of survivin in the human thymus.Hum Immunol. 2002; 63: 101-107Crossref PubMed Scopus (29) Google Scholar, 32Xing Z Conway EM Kang C Winoto A Essential role of survivin, an inhibitor of apoptosis protein, in T cell development, maturation, and homeostasis.J Exp Med. 2004; 199: 69-80Crossref PubMed Scopus (135) Google Scholar survival,33Kornacker M Verneris MR Kornacker B Scheffold C Negrin RS Survivin expression correlates with apoptosis resistance after lymphocyte activation and is found preferentially in memory T cells.Immunol Lett. 2001; 76: 169-173Crossref PubMed Scopus (55) Google Scholar, 34Okada H Bakal C Shahinian A Elia A Wakeham A Suh WK Duncan GS Ciofani M Rottapel R Zuniga-Pflucker JC Mak TW Survivin loss in thymocytes triggers p53-mediated growth arrest and p53-independent cell death.J Exp Med. 2004; 199: 399-410Crossref PubMed Scopus (112) Google Scholar proliferation,32Xing Z Conway EM Kang C Winoto A Essential role of survivin, an inhibitor of apoptosis protein, in T cell development, maturation, and homeostasis.J Exp Med. 2004; 199: 69-80Crossref PubMed Scopus (135) Google Scholar, 35Hikita S Hatano M Inoue A Sekita N Kobayashi K Otaki M Ogasawara T Okada S Hirasawa H Tokuhisa T Overexpression of TIAP/m-survivin in thymocytes enhances cell proliferation.Mol Immunol. 2002; 39: 289-298Crossref PubMed Scopus (17) Google Scholar expansion37Song J So T Cheng M Tang X Croft M Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion.Immunity. 2005; 22: 621-631Abstract Full Text Full Text PDF PubMed Scopus (191) Google ScholarLoss of survivin: T-cell maturation/proliferation defects,28Tripp A Banerjee P Sieburg M Planelles V Li F Feuer G Induction of cell cycle arrest by human T-cell lymphotropic virus type 1 Tax in hematopoietic progenitor (CD34+) cells: modulation of p21cip1/waf1 and p27kip1 expression.J Virol. 2005; 79: 14069-14078Crossref PubMed Scopus (39) Google Scholar, 32Xing Z Conway EM Kang C Winoto A Essential role of survivin, an inhibitor of apoptosis protein, in T cell development, maturation, and homeostasis.J Exp Med. 2004; 199: 69-80Crossref PubMed Scopus (135) Google Scholar mitosis defect28Tripp A Banerjee P Sieburg M Planelles V Li F Feuer G Induction of cell cycle arrest by human T-cell lymphotropic virus type 1 Tax in hematopoietic progenitor (CD34+) cells: modulation of p21cip1/waf1 and p27kip1 expression.J Virol. 2005; 79: 14069-14078Crossref PubMed Scopus (39) Google Scholar; excessive survivin: hyperproliferation,35Hikita S Hatano M Inoue A Sekita N Kobayashi K Otaki M Ogasawara T Okada S Hirasawa H Tokuhisa T Overexpression of TIAP/m-survivin in thymocytes enhances cell proliferation.Mol Immunol. 2002; 39: 289-298Crossref PubMed Scopus (17) Google Scholar lymphoma1Li F Survivin study: what is the next wave?.J Cell Physiol. 2003; 197: 8-29Crossref PubMed Scopus (305) Google Scholar, 2Li F Ling X Survivin study: an update of “What is the next wave?”.J Cell Physiol. 2006; ([E-pub ahead of print])Google Scholar, 3Altieri DC Validating survivin as a cancer therapeutic target.Nat Rev Cancer. 2003; 3: 46-54Crossref PubMed Scopus (1094) Google ScholarBrainBrain development/maturation,35Hikita S Hatano M Inoue A Sekita N Kobayashi K Otaki M Ogasawara T Okada S Hirasawa H Tokuhisa T Overexpression of TIAP/m-survivin in thymocytes enhances cell proliferation.Mol Immunol. 2002; 39: 289-298Crossref PubMed Scopus (17) Google Scholar, 42Pennartz S Belvindrah R Tomiuk S Zimmer C Hofmann K Conradt M Bosio A Cremer H Purification of neuronal precursors from the adult mouse brain: comprehensive gene expression analysis provides new insights into the control of cell migration, differentiation, and homeostasis.Mol Cell Neurosci. 2004; 25: 692-706Crossref PubMed Scopus (90) Google Scholar, 44Altura RA Olshefski RS Jiang Y Boue DR Nuclear expression of survivin in paediatric ependymomas and choroid plexus tumours correlates with morphologic tumour grade.Br J Cancer. 2003; 89: 1743-1749Crossref PubMed Scopus (45) Google Scholar neural cell survival upon injury46Johnson EA Svetlov SI Pike BR Tolentino PJ Shaw G Wang KK Hayes RL Pineda JA Cell-specific upregulation of survivin after experimental traumatic brain injury in rats.J Neurotrauma. 2004; 21: 1183-1195Crossref PubMed Scopus (29) Google Scholar, 48Conway EM Zwerts F Van Eygen V DeVriese A Nagai N Luo W Collen D Survivin-dependent angiogenesis in ischemic brain: molecular mechanisms of hypoxia-induced up-regulation.Am J Pathol. 2003; 163: 935-946Abstract Full Text Full Text PDF PubMed Scopus (91) Google ScholarExcessive survivin: brain-related tumor1Li F Survivin study: what is the next wave?.J Cell Physiol. 2003; 197: 8-29Crossref PubMed Scopus (305) Google Scholar, 2Li F Ling X Survivin study: an update of “What is the next wave?”.J Cell Physiol. 2006; ([E-pub ahead of print])Google Scholar, 3Altieri DC Validating survivin as a cancer therapeutic target.Nat Rev Cancer. 2003; 3: 46-54Crossref PubMed Scopus (1094) Google ScholarLiverLiver regeneration and cell survival49Deguchi M Shiraki K Inoue H Okano H Ito T Yamanaka T Sugimoto K Sakai T Ohmori S Murata K Furusaka A Hisatomi H Nakano T Expression of survivin during liver regeneration.Biochem Biophys Res Commun. 2002; 297: 59-64Crossref PubMed Scopus (61) Google Scholar, 16Conway EM Pollefeyt S Steiner-Mosonyi M Luo W Devriese A Lupu F Bono F Leducq N Dol F Schaeffer P Collen D Herbert JM Deficiency of survivin in transgenic mice exacerbates Fas-induced apoptosis via mitochondrial pathways.Gastroenterology. 2002; 123: 619-631Abstract Full Text Full Text PDF PubMed Scopus (91) Google ScholarExcessive survivin: liver-related cancer1Li F Survivin study: what is the next wave?.J Cell Physiol. 2003; 197: 8-29Crossref PubMed Scopus (305) Google Scholar, 2Li F Ling X Survivin study: an update of “What is the next wave?”.J Cell Physiol. 2006; ([E-pub ahead of print])Google Scholar, 3Altieri DC Validating survivin as a cancer therapeutic target.Nat Rev Cancer. 2003; 3: 46-54Crossref PubMed Scopus (1094) Google ScholarPancreasFetal islet development/maturation52Liggins C Orlicky DJ Bloomquist LA Gianani R Developmentally regulated expression of survivin in human pancreatic islets.Pediatr Dev Pathol. 2003; 6: 392-397Crossref PubMed Scopus (20) Google ScholarExcessive survivin: pancreatitis?53Tashiro M Nakamura H Taguchi M Yoshikawa H Otsuki M Expression of survivin after acute necrohemorrhagic pancreatitis in rats.Pancreas. 2003; 26: 160-165Crossref PubMed Scopus (9) Google Scholar pancreatic cancer1Li F Survivin study: what is the next wave?.J Cell Physiol. 2003; 197: 8-29Crossref PubMed Scopus (305) Google Scholar, 2Li F Ling X Survivin study: an update of “What is the next wave?”.J Cell Physiol. 2006; ([E-pub ahead of print])Google Scholar, 3Altieri DC Validating survivin as a cancer therapeutic target.Nat Rev Cancer. 2003; 3: 46-54Crossref PubMed Scopus (1094) Google Scholar, 54Qiao JG Zhang YQ Yin YC Tan Z Expression of survivin in pancreatic cancer and its correlation to expression of Bcl-2.World J Gastroenterol. 2004; 10: 2759-2761Crossref PubMed Scopus (29) Google ScholarGastrointestinal tractEpithelial cell renewal,55Chiou SK Moon WS Jones MK Tarnawski AS Survivin expression in the stomach: implications for mucosal integrity and protection.Biochem Biophys Res Commun. 2003; 305: 374-379Crossref PubMed Scopus (63) Google Scholar cell survival56Chiou SK Tanigawa T Akahoshi T Abdelkarim B Jones MK Tarnawski AS Survivin: a novel target for indomethacin-induced gastric injury.Gastroenterology. 2005; 128: 63-73Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 62Zhang T Otevrel T Gao Z Ehrlich SM Fields JZ Boman BM Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer.Cancer Res. 2001; 61: 8664-8667PubMed Google ScholarExcessive survivin: gastrointestinal tumorigenesis1Li F Survivin study: what is the next wave?.J Cell Physiol. 2003; 197: 8-29Crossref PubMed Scopus (305) Google Scholar, 2Li F Ling X Survivin study: an update of “What is the next wave?”.J Cell Physiol. 2006; ([E-pub ahead of print])Google Scholar, 3Altieri DC Validating survivin as a cancer therapeutic target.Nat Rev Cancer. 2003; 3: 46-54Crossref PubMed Scopus (1094) Google Scholar, 19Li F Role of survivin and its splice variants in tumorigenesis.Br J Cancer. 2005; 92: 212-216Crossref PubMed Scopus (21) Google ScholarTestisSpermatogenesis63Wang Y Suominen JS Hakovirta H Parvinen M Martinand-Mari C Toppari J Robbins I Survivin expression in rat testis is upregulated by stem-cell factor.Mol Cell Endocrinol. 2004; 218: 165-174Crossref PubMed Scopus (24) Google Scholar, 64Weikert S Schrader M Muller M Krause H Miller K Expression of the apoptosis inhibitor survivin in testicular tissue of infertile patients.Int J Androl. 2004; 27: 161-165Crossref PubMed Scopus (25) Google ScholarLoss of survivin: spermatogenic failure64Weikert S Schrader M Muller M Krause H Miller K Expression of the apoptosis inhibitor survivin in testicular tissue of infertile patients.Int J Androl. 2004; 27: 161-165Crossref PubMed Scopus (25) Google Scholar, 65Weikert S Schrader M Muller M Schulze W Krause H Miller K Expression levels of the inhibitor of apoptosis survivin in testes of patients with normal spermatogenesis and spermatogenic failure.Fertil Steril. 2005; 83: 1100-1105Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 66Weikert S Christoph F Schulze W Krause H Kempkensteffen C Schostak M Miller K Schrader M Testicular expression of survivin and human telomerase reverse transcriptase (hTERT) associated with spermatogenic function in infertile patients.Asian J Androl. 2006; 8: 95-100Crossref PubMed Scopus (16) Google Scholar; excessive survivin: tumorigenesis67Weikert S Schrader M Krause H Schulze W Muller M Miller K The inhibitor of apoptosis (IAP) survivin is expressed in human testicular germ cell tumors and normal testes.Cancer Lett. 2005; 223: 331-337Abstract Full Text Full Text PDF PubMed Scopus (24) Google ScholarEndometriumEndometrial homeostasis?69Konno R Yamakawa H Utsunomiya H Ito K Sato S Yajima A Expression of survivin and Bcl-2 in the normal human endometrium.Mol Hum Reprod. 2000; 6: 529-534Crossref PubMed Google ScholarExcessive survivin: endometriosis,70Ueda M Yamashita Y Takehara M Terai Y Kumagai K Ueki K Kanda K Yamaguchi H Akise D Hung YC Ueki M Survivin gene expression in endometriosis.J Clin Endocrinol Metab. 2002; 87: 3452-3459Crossref PubMed Scopus (78) Google Scholar endometriotic cysts,73Goteri G Lucarini G Pieramici T Filosa A Pugnaloni A Montik N Biagini G Tranquilli AL Fabris G Ciavattini A Lo Muzio L Endothelial cell survivin is involved in the growth of ovarian endometriotic cysts.Anticancer Res. 2005; 25: 4313-4318PubMed Google Scholar or cancer1Li F Survivin study: what is the next wave?.J Cell Physiol. 2003; 197: 8-29Crossref PubMed Scopus (305) Google Scholar, 2Li F Ling X Survivin study: an update of “What is the next wave?”.J Cell Physiol. 2006; ([E-pub ahead of print])Google Scholar, 3Altieri DC Validating survivin as a cancer therapeutic target.Nat Rev Cancer. 2003; 3: 46-54Crossref PubMed Scopus (1094) Google Scholar, 71Takai N Miyazaki T Nishida M Nasu K Miyakawa I Survivin expression correlates with clinical stage, histological grade, invasive behavior and survival rate in endometrial carcinoma.Cancer Lett. 2002; 184: 105-116Abstract Full Text PDF PubMed Scopus (103) Google Scholar, 72Pallares J Martinez-Guitarte JL Dolcet X Llobet D Rue M Palacios J Prat J Matias-Guiu X Survivin expression in endometrial carcinoma: a tissue microarray study with correlation with PTEN and STAT-3.Int J Gynecol Pathol. 2005; 24: 247-253Crossref PubMed Scopus (52) Google ScholarPlacentaPlacenta homeostasis?74Shiozaki A Kataoka K Fujimura M Yuki H Sakai M Saito S Survivin inhibits apoptosis in cytotrophoblasts.Placenta. 2003; 24: 65-76Abstract Full Text PDF PubMed Scopus (36) Google Scholar cell survival?76Ka H Hunt JS Temporal and spatial patterns of expression of in-hibitors of apoptosis in human placentas.Am J Pathol. 2003; 163: 413-422Abstract Full Text Full Text PDF PubMed Scopus (65) Google ScholarExcessive survivin: hydatidiform mole75Lehner R Bobak J Kim NW Shroyer AL Shroyer KR Localization of telomerase hTERT protein and survivin in placenta: relation to placental development and hydatidiform mole.Obstet Gynecol. 2001; 97: 965-970Crossref PubMed Scopus (42) Google Scholar Open table in a new tab Observations that targeting survivin for cancer therapy appears to cause little toxicity to normal tissues is obviously not the final answer to the question of toxicity raised above; these results, however, do indicate the possibility that the regulation and/or the signaling interactions of survivin may show differences between cancer cells and normal cells. Consistent with this possibility, it has been shown that survivin antibodies are readily detectable in sera from cancer patients but not in normal human sera (reviewed in Ref. 1Li F Survivin study: what is the next wave?.J Cell Physiol. 2003; 197: 8-29Crossref PubMed Scopus (305) Google Scholar). Moreover, another difference, which may contribute to an effective therapeutic index in cancer cells, is that cancer cells have a mitochondrial pool of survivin, whereas normal cells do not. The mitochondrial pool of survivin has been shown to be critical for mediating inhibition of cancer cell apoptosis.10Dohi T Beltrami E Wall NR Plescia J Altieri DC Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis.J Clin Invest. 2004; 114: 1117-1127Crossref PubMed Scopus (339) Google Scholar In addition, it is known that many critical molecules in cell survival pathways such as Akt, Erk, and EGFR are highly active in cancer cells compared with that in normal cells. These molecules have been shown to promote the expression of survivin,1Li F Survivin study: what is the next wave?.J Cell Physiol. 2003; 197: 8-29Crossref PubMed Scopus (305) Google Scholar, 11Wang Q Greene MI EGFR enhances survivin expression through the phosphoinositide 3 (PI-3) kinase signaling pathway.Exp Mol Pathol. 2005; 79: 100-107Crossref PubMed Scopus (34) Google Scholar, 12Qiu L Wang Q Di W Jiang Q Schefeller E Derby S Wanebo H Yan B Wan Y Transient activation of EGFR/AKT cell survival pathway and expression of survivin contribute to reduced sensitivity of human melanoma cells to betulinic acid.Int J Oncol. 2005; 27: 823-830PubMed Google Scholar thus providing another difference from normal cells that may permit for therapeutic efficacy of targeting survivin with acceptable toxicities. We have previously shown that DNA-protein interactions in the survivinpromoter region differ between nuclear proteins isolated from cancer cells and those from normal cells.1Li F Survivin study: what is the next wave?.J Cell Physiol. 2003; 197: 8-29Crossref PubMed Scopus (305) Google Scholar Collectively, these observations provide new perspectives on survivin as a valid therapeutic target for treatment of cancer and other diseases and suggest new research directions at two levels: 1) investigation of the differential regulation and/or signaling interactions of survivin between cancer and normal cells; and 2) determination of the underlying molecular mechanisms of these differences. These studies would certainly be important because the results derived from them might enable novel strategies to treat different diseases without toxicity to normal human tissues. The current available information about the role for survivin in the pathophysiology of various human normal cells and/or organs has been collected in this Review (see Table 1 for an overview) in the hope of facilitating potential studies for optimizing low-toxicity disease treatments by targeting survivin. In addition, we have also provided our opinions regarding future studies of the potential value based on the highlighted data from the references. Survivin is expressed in a strictly regulated manner during embryonic development13Adida C Crotty PL McGrath J Berrebi D Diebold J Altieri DC Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation.Am J Pathol. 1998; 152: 43-49PubMed Google Scholar, 14Murphy CR Sabel JL Sandler AD Dagle JM Survivin mRNA is down-regulated during early" @default.
• W684291 created "2016-06-24" @default.
• W684291 creator A5012581623 @default.
• W684291 creator A5027674029 @default.
• W684291 date "2006-07-01" @default.
• W684291 modified "2023-10-12" @default.
• W684291 title "Role of the SurvivinGene in Pathophysiology" @default.
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• W684291 doi "https://doi.org/10.2353/ajpath.2006.060121" @default.
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